Mechanisms involved in neuroprotective effects of transcranial magnetic stimulation

: Transcranial magnetic stimulation (TMS) is widely used in neurophysiology to study cortical excitability. Research over the last few decades has highlighted its additional value as a potential therapeutic tool in the treatment of a broad range of psychiatric disorders. More recently, a number of studies have reported beneficial and therapeutic effects for TMS in neurodegenerative conditions and strokes. Yet despite its recognised clinical applications and despite considerable research using animal models, the molecular and physiological mechanisms through which TMS exerts its beneficial and therapeutic effects remain unclear. They are thought to involve biochemical-molecular events affecting membrane potential and gene expression. In this aspect, the dopaminergic system plays a special role. This is the most directly and selectively modulated neurotransmitter system, producing an increase in the flux of dopamine (DA) in various areas of the brain after the application of repetitive TMS (rTMS). Other neurotransmitters, such as glutamate and gamma-aminobutyric acid (GABA) have shown a paradoxical response to rTMS. In this way, their levels increased in the hippocampus and striatum but decreased in the hypothalamus and remained unchanged in the mesencephalon. Similarly, there are sufficient evidences that TMS up-regulates the gene expression of BDNF (one of the main brain neurotrophins). Something similar occurs with the expression of genes such as c-Fos and zif268 that encode trophic and regenerative action neuropeptides. Consequently, the application of TMS can promote the release of molecules involved in neuronal genesis and maintenance. This capacity may mean that TMS becomes a useful therapeutic resource to antagonize processes that underlie the previously mentioned neurodegenerative conditions.

Paradoxical immune reconstitution inflammatory syndrome in neurotuberculosis

Tuberculosis (TB) remains the most common infection in developing countries and India contributes the maximum number of cases to the global burden. Primary healthcare physicians across the country face major challenges in diagnosis and treatment of childhood TB. In this context, clinical cases of paradoxical responses to antitubercular therapy seem to be under-reported. We report a case of tubercular meningitis in an adolescent girl who belonged to a remote village. She developed a paradoxical immune response to TB while on anti-TB treatment (ATT). She presented with raised intracranial tension and neurological deficits during the continuation phase of ATT after stopping corticosteroids. The ring-enhancing lesions of tuberculomas in the brain and spine characterised the diagnosis of paradoxical response to TB. Brain biopsy suggested necrotising granulomatous disease and was negative for S100 and CD1a marker, ruling out active TB. Retreatment with a prolonged course of steroids and ATT resulted in the clinical and radiological recovery, though some motor and visual deficits persisted. Clinical risk factors and socioeconomic factors also contributed to the present state of the child.

Severe restless legs syndrome in a family with Alport syndrome

Background Restless legs syndrome (RLS) is a common sleep-related movement disorder characterized by an urge to move the legs during inactivity, especially at evening-night. RLS is highly prevalent in patients with kidney failure and have an impact on quality of life, mood, sleep quality and overall on compliance to the dialysis. Alport syndrome (AS) is a rare inherited disease, predominantly X-linked, secondary to mutations in genes encoding α3, α4 or α5 chains of type IV collagen, and characterized by hematuria, chronic kidney disease, neurosensory deafness, and lenticonus. Case presentation Here we describe a family with a combination of X-linked AS and severe RLS accompanied by periodic limb movements during sleep (PLMS). In the first patient we identified, RLS was complicated by a paradoxical response to dopamine agonists named “augmentation”, leading to sleep disruption, hallucinations and five peritoneal perforations during the peritoneal dialysis due to the difficulty to rest still. Therapeutic adjustments and renal transplantation improved RLS and PLMS. In two brothers, severe RLS prevented a compliance with hemodialysis. Female family members carrying the mutation were also affected by RLS, while those without the mutations were RLS-free. Conclusions RLS has not been reported earlier in association with AS, but the peculiar combinations observed in this family will stimulate further clinical studies and motivate nephrologists to seek for RLS symptoms and sleep disturbances in AS patients.

Paradoxical Response of Pulmonary Slowly Adapting Units During Constant Pressure Lung Inflation

Typically, unit discharge of slowly adapting receptors (SARs) declines slowly when lung inflation pressure is constant, although in some units it increases instead-a phenomenon hereinafter referred to as creeping. These studies characterize creeping behavior observed in 62 of 137 SAR units examined in anesthetized, open-chest and mechanically ventilated rabbits. SAR units recorded from the cervical vagus nerve were studied during 4 seconds of constant lung inflation at 10, 20 and 30 cmH2O. Affected SAR units creep more quickly as inflation pressure increases. SAR units also often deactivate after creeping, i.e., their activity decreases or stops completely. Creeping likely results from encoder switching from a low discharge to a high discharge SAR, because it disappears in SAR units with multiple receptive fields after blocking a high discharge encoder in one field leaves low discharge encoders intact. The results support that encoder switching is a common mechanism operating in lung mechanosensory units.

Abstract MP43: Paradoxical Response to Antibodies in Periodontal Microbes in Subjects With Intracranial Atherosclerotic Stenosis

Introduction: Previously we have shown that periodontal disease and systemic inflammation are related to intracranial atherosclerosis (ICAS) in Atherosclerosis Risk In Communities study (ARIC). In this study we evaluated the relationship between serum antibodies against periodontal pathogens and ICAS. Methods: In this ongoing, prospective, longitudinal community-based cohort study, participants were assessed for antibodies to periodontal organisms including Porphyrmonas gingivalis (PG), Prevotella intermedia (PI), Prevotella nigrescens (PN), Bacteriodes forsythensis (BF), Treponema denticola (TD), Actinobacillus actinomycetemcomitans (AA), Campylobacter rectus (CR), Eikenella corrodens (EC), Fusobacterium nucleatum (FN), Peptostreptococcus micros (PM), Selenomonas noxia (SN), Capnocytophaga ochracea (CO), Veillonella parvula (VP), Streptococcus sanguinis (SS), Streptococcus intermedius (SI), Streptococcus oralis (SO), Actinomycosis viscosis (AV) and Helicobacter pylori (HP). These participants underwent 3D time-of-flight magnetic resonance angiography (MRA) to evaluate ICAS. Log mean antibody (IgG), CRP and IL-6 levels were compared using t-test between groups with and without ≥50% ICAS. Results: In this ARIC cohort, 1066 participants were assessed by MRA for ICAS. Serum CRP and IL-6 data were available for all and IgG levels were available for 772 participants. The log mean IgG level was significantly lower for patients with ≥50% ICAS versus patients with <50% ICAS in four organisms: PN (1.69 vs 1.80, p= 0.03 ), BF (1.30 vs 1.38, p=0.05 ), CO (1.23 vs 1.33, p= 0.04 ), FN (0.87 vs 1.01, p=0.02 ). The log mean IgG was also lower for CR, EC, SN, VP, SI, SO and AV though not significant. Log mean CRP was higher in the ≥50% ICAS group versus the <50% ICAS group (0.58 vs. 0.47, p < 0.001 ). Log mean IL-6 levels were also higher but not significant (0. 17 vs. 0.11, p= 0.07 ). Conclusion: Higher levels of systemic inflammatory markers (CRP, IL-6) are associated with significant ICAS, but we report a significantly lower level of IgG antibodies to specific periodontal pathogens (PN, BF, CO and FN) in patients with ≥50% ICAS. This paradoxical finding may represent the effect of systemic inflammation and oxidative stress on IgG levels to periodontal bacteria.

Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2−/− mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2−/− mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2−/− mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.

Prevalence of Subclinical Carotid Atherosclerosis and Associated Risk Factors in Individuals Without Cardiovascular Risk Factors: Insights from General Population

Objective: Individuals without conventional cardiovascular risks (CVRFs) still have the risk of adverse outcomes, and subclinical carotid atherosclerosis is a known predictor of cardiovascular events. We aimed to assess the prevalence and associated risk factors of subclinical carotid atherosclerosis in CVRF-free population. Methods: The cross-sectional study was conducted in rural northeast China in 2017-2018. CVRFs freedom was defined as untreated blood pressure < 140/90 mmHg, fasting plasma glucose < 7.0 mmol/L, untreated total cholesterol < 6.22 mmol/L, low-density lipoprotein cholesterol < 4.14 mmol/L, high-density lipoprotein cholesterol (HDL-C) ≥ 1.04 mmol/L, and no current smoking. This subgroup population included 1449 individuals, and ultrasound was used to detect carotid atherosclerosis. Results: The mean carotid intima-media thickness is 0.74 ± 0.14 mm. The prevalence of carotid plaque is 23.4% (95%CI: 21.2%-25.6%) among CVRFs-free population, significantly higher in men than in women (37.1% vs 20.0%, p<0.001), and rises steeply with advancing age. 1.31% have moderate-to-severe carotid stenosis. Advancing age, man, glycosylated hemoglobin (OR, 1.90; 95% CI, 1.20-1.32), HDL-C level (OR, 2.31; 95% CI, 1.75-3.04), and pulse pressure (OR, 1.03; 95% CI, 1.01-1.05) are potentially related to presence of carotid atherosclerosis. Adjusted-dose-response association shows a linear relationship between HDL-C and prevalence of carotid atherosclerosis. Conclusions: The prevalence of subclinical carotid atherosclerosis in CVRF-free population was relatively high, indicating poorly defined factors might contribute to the early atherogenesis. Moreover, we observed a paradoxical response between subclinical carotid atherosclerosis and HDL-C levels, suggesting that treatment targeting to increase HDL-C levels might not reduce future cardiovascular risks.

RBIO-03. HETEROGENEITY OF HUMAN PATIENT-DERIVED XENOGRAFTS GROWTH RATES RESPONSES TO THE RADIATED MICROENVIRONMENT

BACKGROUND Radiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumors are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics. METHODS Female athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected patient-derived xenograft (PDX) GBM cell lines (GBM 6, 10, 12, 39, 46, 76, 123, 164, 196; total n=8-15, per group, per line). Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups. RESULT Of nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196). However, two lines yielded prolonged survival in the pre-radiated brain (GBM 10, 12); GBM 39, 123 whose rate of growth was not impacted by the radiated brain. CONCLUSION These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.